: A reduction in the mass of B-cells in the pancreas is an important causative factor in the pathogenesis of both type 1 and type 2 diabetes. The understanding of the factors and mechanisms involved in neogenesis and proliferation of B-cells will help direct therapies focused on re-establishment of a functional 13-cell mass. Glucagon-like peptide 1 (GLP-1) and its long acting agonist, Exendin-4, stimulate both the differentiation of B-cells from ductal progenitor cells (neogenesis) and the proliferation of B-cells. Exendin-4 also stimulates expression of PDX- 1 (a master regulator of pancreas development) in exocrine pancreas. Overexpression of PDX-1 in the exocrine pancreas increases replication rates and promotes greater response of B-cells to glucose. The goal of this grant is to investigate the role of endogenous GLP-1 in B-cell growth and to explore the mechanisms underlying GLP-1 stimulated islet growth. Our unifying hypothesis is that GLP-1 augments B-cell neogenesis and proliferation by stimulating PDX-1 expression. Further, we hypothesize that GLP-1 may function as a normal signal from the intestine to the pancreas to regulate the B-cell mass required to metabolize ingested nutrients. To test these hypotheses, an antagonist of GLP-l receptor will be used to block GLP-1 action in mice after partial pancreatectomy. In a parallel approach, we will evaluate pancreatic regeneration in a GLP-1 receptor null mouse model. Glucose tolerance, PDX-1 expression, rates of proliferation, rates of neogenesis and B-cell mass will be studied in this model. The effect of over expression of PDX-1 in the exocrine tissue will be also studied. Studies in vivo and in vitro will be conducted to identify genes